Gram-negative bacteria that are resistant to aminoglycoside, β-lactam, and fluoroquinolone antibiotics are increasingly common. These bacteria are often susceptible to the polymyxins and related peptides having antibacterial properties (Refs. 1, 10, 23). As a result, there is interest in the use of polymyxins for multidrug-resistant gram-negative bacterial infections in humans (Ref. 23).
Peptides such as polymyxin B and the related colistin (polymyxin E) have been administered to humans as antibacterial agents. However, their use has been previously restricted because of their toxicity. These peptides comprise a seven amino acid cyclic peptide attached to an exocyclic three amino acid chain, wherein the N-terminal amine of the exocyclic chain is linked to a “side chain” or “tail”. The tail is most commonly an acyl group.
Some renal toxicity has been observed with the recommended dosing of polymyxin B in patients. Neurotoxicity has also been observed in patients with compromised renal functions, with an overall incidence of 7.3% reported in one large study with colistin (Ref. 1). The acyl exocyclic chain and the adjacent N-terminal 2,4-diaminobutanoic acid (Dab) residue can be enzymatically removed from polymyxin, thereby yielding the corresponding nonapeptide. The in vivo toxicity of the nonapeptide of polymyxin B is significantly less than that of polymyxin B itself (Ref. 16). The toxicity of the nonapeptide in cell culture is reduced by about 100-fold relative to polymyxin B; however, the antibacterial activity of the nonapeptide is also reduced by about 2-64 fold relative to polymyxin B (Ref. 11).
Attempts have been made to chemically modify polymyxin and colistin in order to obtain peptides with improved antibacterial properties. For example, the total synthesis of polymyxin B and four analogs was previously accomplished by a combination of solid phase peptide syntheses to obtain linear structures, followed by removal from the resin and condensation in solution at high dilution to obtain the cyclic peptide structure (Ref. 7). The derivatives, however, were less active than polymyxin B. A more recent total synthesis of polymyxin B and a few closely related compounds was accomplished only by solid phase peptide synthesis (Refs. 15, 26). Although both of these solid phase total synthetic approaches can provide new derivatives of polymyxin, these methods appear limited since the quantities of antibiotic produced are small and require large amounts of amino acid precursors. Any scale up of these methods for clinical studies may prove to be difficult and costly.
Accordingly, there remains an ongoing need for new peptide compounds having antibacterial properties, and new methods for preparing such compounds.